Antirigor thioxanthenes



United States Patent 3,179,564 ANTIRIGOR THIOXANTHENES Jean Schmutz,Muri, near Bern, Switzerland, assignor to Dr. A. Wander, S.A., Bern,Switzerland, a Swiss corporation No Drawing. Original application Feb.23, 1961, Ser. No. 90,943. Divided and this application Apr. 16, 1962,Ser. No. 187,952

5 Claims. (Cl. 167-65) This application is a continuation-in-partapplication of my US. application Serial No. 860,078, filed December 17,1959, and a divisional application of my US. application Serial No.90,943, filed February 23, 1961, both now abandoned.

This invention relates generally to new therapeutic compositions and toa novel method of treating a living animal to reduce rigor. Moreparticularly, the present invention relates to a novel therapeuticcomposition in dosage unit form comprising9-(N-alkyl-piperidyl-alkyl)-thioxanthenc compounds and to the use ofthis compositionto reduce rigor by introducing it into the body of aliving animal.

In my US. Patent No. 2,905,590 the novel compound9-(N-methyl-piperidyl-3'-methyl)-thioxanthene and the acid salts thereofhaving anti-Parkinson activityare disclosed. It has now beenunexpectedly discovered that certain other thioxanthene derivatives andthe acidaddition salts thereof have important antirigor activity oftherapeutic value which is entirely lacking in the patented compounds.

The novel thioxanthene compounds of the present invention which haveantirigor activity are the bases of the class consisting of9-(N-ethyl-piperidyl-3'-methyl)-thio- Xanthene, 9 (Nn-propylpiperidyl-3-methyl)-thioxanthene, and 9 (Nmethyl-piperidyl-ZHB-ethyl)thioxanthene; and the acid addition salts ofthese bases.

The bases described above are organic bases which can be reactedwithacids to form readily water-soluble salts useful for oral or parenteraltherapy. Although the free bases are the source of the pharmacologicalutility of the compounds, it is generally more convenient to employ thesalts, particularly the hydrochlorides and the tartrates. The salts areformed by well-known techniques, e.g., by neutralizing an ether oralcohol solution of the bases with an acetone or alcohol solution of thedesired acid and recrystallising the resultant salts from awater-acetone or an alcohol-ether solution. In forming salts ofinorganic acids, it ispreferred to employ hydrochloric acid, sulfuricacid, or phosphoric acid. Among the organic acids which can be used forforming salts with good results are acetic acid, maleic acid, tartaricacid and citric acid.

It has been found that the new compounds described above have a specificeifect on the central nervous system which can be designated morespecifically as antirigor activity. This activity is completely absentin the 9- (N- methyl-piperidyl-3-methyl)-thioxanthene described in US.patent specification No. 2,905,590.

The antirigor effect was tested on decerebrate rats according to themethod of C. S. Sherrington [Ciba Foundation Symposium on theneurological basis of behaviour, page 55 if. (1958)], using rats astestanimals. The rigor occuring in the muscles of decerebrate rats is notdecreased upon intravenous administration of therapeutical doses of9-(N-methyl-piperidyl-3'-methyl)-thioxanthene, whereas the higherhomologues thereof described above 33,179,554 Patented Apr. 20, 1965"Ice are effective in very small amounts, as shown in the followingtable: I

ANTI-RIGOR EFFECT IN THE MYOGRAM OF DE- CEREBRATE RATS ACCORDING TO C.S. SHER- RINGTON Minimum amount Compound tested necessary for 30% de-Il.D./50,

The new compounds described before can be employed 1 in the usual formsfor therapeutic administration. For example, the active substances maybe combined with a suitable pharmaceutical carrier to provide solutions,syrups, tablets, capsules, dragees, suppositories, powders, or the like.The dosage unit form may contain from about five to one hundred mg. ofthe active substance. In the case of solutions for intravenousinjection, the ampoule may contain, by way of illustration, 0.5 to 3%solution, since very small amounts are elfective when a solution thereofis injected intravenously. For infusion, the ampoule may contain a 2 to3% solution with fifty to one hundred mg. of active substance perampoule. In the case of tablets or the like the dosage of activesubstance may be five to fifty mg. and for suppositories twenty to onehundred milligrams.

For administering the compounds ofthis invention, the oral routeisnormally preferred, tablets containing five to ten mg. of activesubstance being given four to six times during one day, so that thepatient will receive a total daily dose of twenty to sixty mg.ofthioxanthene compound.

The synthesis of the new compounds of the present invention is carriedout conveniently by first metallising the thioxanthene in the 9 positionand then reacting the resultant metallothioxanthene compound with anester of an alcohol of the class consisting of N-ethyl-piperidyl-S-methanol, N-n-propyl-piperidyl-3-methanol and fi-(N-methyl-piperidyl-3)-ethanol, and particularly an ester thereof of ahydrochloric acid, such as hydrochloric or hydrobromic acid, or of anaryl sulfonic acid, particularly benzene sulfonic acid or p-toluenesulfonic acid. The resulting esters of the foregoing alcohols have thefollowing general formulae, respectively:

wherein X represents a halogen molecule, especially chlorine or bromine,or an alkyl sulfonate, particularly benzene sulfonate or p-toluenesulfonate. The reaction is preferably carried out in an inert solventsuch as benzene, toluene, dioxane, anisole, etc. The preferredmetallising agents are the alkali metal compounds such as aryl sodium,particularly phenyl sodium and tolyl sodium, sodium amide, aryl lithium,alkyl lithium etc. Usually, phenyl sodium, tolyl sodium, and sodiumamide will be usedbecause of their relative cheapness and availability.Both reactions can be carried out simultaneously if desired, i.e., thethioxanthene, the metallising agent and the ester can all be reactedtogether.

i A further method of preparation of the new compounds of the presentinvention consists in hydrogenating a compound of one of the followingformulae:

If desired, a dehydration product of the foregoing 9-hydroxy compoundscan be used in place of the 9-hydroxy compound. The hydrogenatoinreaction can be carried out with nascent hydrogen, preferably by the useof sodium and an alcohol, or by catalytically hydrogenating. The9-hydroxy thioxanthene starting material of this method can'be producedby reacting a suitably substituted thioxanthene with a l-ethylor1-n-propyl-piperidino-3- methyl-metallo compound or a l-methylpiperidino-2- ethyl-metallo compound respectively, for instance with aGrignard compound, according to known methods.

The following specific examples illustrate methods of preparation of thecompounds of the present invention but should not be construed torestrict the invention to the particular reactants or proportionsemployed.

Example 1.--9-(N-e thyl-piperidyl- '-methyl) -thioxanthene To a sodiumdispersion of 4.9 gm. of finely pulverized sodium in 50 ml. of absolutebenzene is added dropwise with stirring 12 gm. of chlorobenzene in 50ml. of absolute benzene. As soon as the exothermic reaction begins, thetemperature is maintained between 30 and 35 C. by cooling, and stirringis continued for two to three hours.

To the resulting phenyl sodium solution is added dropbenzene. Theslightly exothermic reaction ceases after about one to one-and-a-halfhours.

l heated to 40 C. for one hour. The resulting mixture is decomposedbyadding carefully a small amount of water,

and the newly formed base is extracted from the benzene solution bymeans of dilute hydrochloric acid. The

aqueons'hydrochloric acid solution is made alkaline by Example2.+9-(N-n-propyl-piperidyl-S-methyl)- thz'oxanthene By following thesame procedure as in Example 1, but using instead of theN-ethyl-3-chloromethyl-piperidine, 13.9 gm. ofN-n-propyl-3-chloromethyl-piperidine, a yield of 22.0 gm. of the base,9-(N-n-propyl-piperidyl-3-rnethyl)-thioxanthene, is obtained, said basehaving a boiling wise 19.8 gm. of thioxanthene in 120 ml. of absolute Tothe latter freshly prepared 9-thioxanthyl sodium point of 178 to 181 C./0.07 mm.

Example 3.9-(N-methyl-piperidyl-Z'fi-ethyl) -thioxanthene By followingthe same procedure as in Example 1, but using instead of theN-ethyl-3-chloromethyl-piperidine, 13.5 gm. ofN-methyl-2-fi-chloroethyl-piperidine, a yield of 21.7 gm. of the base,9-(N-methyl-piperidyl-2'-,B-ethyl)- thioxanthene, is obtained, said basehaving a boiling point of 176 to 179 C./0.07 mm.

Example 4.9-(N-ethyl-piperidyl-3-methyl)-thi0xa1ithene hydrochloridesalt An ether solvent solution of 9-(N-ethyl-piperidyl-3'-methyl)-thioxanthene is neutralized with an alcoholic solution ofhydrogen chloride to form the9-(N-ethylpiperidyl-3'-methyl)-thioxanthene hydrogen chloride salt whichis crystallised upon addition of ether to give the said salt in the formof colourless prismatic crystals, said salt exhibiting a melting pointof 197 to 199 C.

Example 5.9-(N-n-pr0pyl-piperidyl-3-methyl)-thi0- xanthene hydrochloridesalt By following the same procedure as in Example 4, but using insteadof the 9-(N-ethyl-piperidyl-3-methyl)-thioxanthene 9(N-napropyl-piperidyl-li'-methy1)-thioxan-- thene, the correspondinghydrochloride salt is obtained in the form of colourless, prismaticcrystals, said salt exhibiting a melting point of 203 to 206 C.

Example 6.--9-(N-methyl-piperidyl-Z'-B-ethyl)-thi0- xanthenehydrochloride salt 7 An ether solvent solution of9-(N-methyl-piperidyl-2- fl-ethyD-thioxanthene is neutralized with asuitable organic solvent solution of hydrogen chloride, suchas an etherhydrogen chloride solution, to form the9-(N-methylpiperidyl-T-B-ethyl)-thioxanthene hydrachloride salt, whichis recrystallised from an acetone-ether solution to give the said saltin the form of colourless, prismatic crystals, said salt exhibiting amelting point of 173 to Example 7.9-(N-ethyl-piperidyl-3-methyl)-thioxanthene Thioxanthene is reacted with 1-ethyl-piperidino-3- methylmagnesium chloride according to known methods (cf. A. Marker, Helv.chim. Acta 24 E, 209 [1941] to form9-(N-ethyl-piperidino-3-methyl)-thioxanthenol(9). Ten parts. of thecrude product are dissolved in two.

hundred parts of propanol. The solution is heated to gentle reflux, andfive parts of sodium chips are added in small increments with stirring.After thefsodiurn isv completely added, the solvent is removed bydistillation. The residue is combined With Water and extracted withether. After evaporation of the solvent, the residue is distilled invacuo. the base, 9-(N-ethyl-piperidyl'-methyl) thioxanthene,

A viscous alkaline product comprising 5 having the boiling point 175 to178 C./0.07 mm., is obtained in a yield of 85 to 90% of the theoretical.Upon acidification with alcoholic hydrochloric acid and addition ofether (1:2) the hydrochloride addition salt of said base crystallises incolourless prisms, said salt having a melting point 197 to 1990 C.

Example 8.-Preparatin of tablets containing mg. of

9 -(N -ethyl piperidyl 3'-methyl)-thi0xanthene hydrochloride 0.500 kg.of 9-(N-ethyl-piperidyl-3-methyl)-thioxanthene hydrochloride and 14.500kg. of lactose are mixed. The mixture is kneaded with 0.080 kg. ofparaffin oil, 0.010 kg. of sodium alginate (dissolved in 1450 ml. ofwater) and 350 ml. of water and granulated through Colton screen N0. 16.The granulate is dried during 24 hours at 50 C. and then passed throughColton screen No. 16. The moisture content of the granulate should notexceed 0.4% (as measured with the infra-red lamp, position 3, weak,minutes).

15.090 kg. of the granulate are mixed with 1.450 kg. of maize-starch and1.460 kg. of talcum, and the mixture is compressed into tablets, using aHamming-machine with 8 mm. fiat die having a pressed border and dividinggroove (double set). In this way, 100,000 tablets are produced, havingthe following properties:

Tablet weight 0.18 g.

Thickness 2.4 to 2.6 mm.

Disintegration About 1 minute.

Resistance to compression At least 3 kg.

Loss from rotation Maximum 1.0%.

I claim:

1. A therapeutic composition in dosage unit form comprising apharmaceutical carrier and from about 5 to about 100 mg. of a compoundselected from the group consisting of9-(N-methyl-piperidyl-2'-,8-ethyl)-thioxanthene, and thepharmaceutically acceptable acid addition salts thereof.

2.A therapeutic composition as in claim 1 wherein the compound is9-(N-methyl-piperidy1-2'-,B-ethyl)-thioxanthene, said composition havingmarked therapeutic antirigor activity when administered to a livinganimal.

3. A therapeutic composition as in claim 1 wherein the compound is apharmaceutically acceptable acid addition salt of9-(N-methyl-piperidyl-2'-B-ethyl)-thioxanthene, said composition havingmarked therapeutic antirigor activity when administered to a livinganimal.

4. A method of treating a living animal to reduce rigor which comprisesintroducing into the body of a living animal effective amounts of acompound selected from the group consisting of9-(N-methyl-piperidyl-2'-fl-ethyl)- thioxanthene, and thepharmaceutically acceptable acid addition salts thereof.

5. A method as in claim 4 wherein said compound is introduced into saidbody in an amount of at least about 0.1 mg. kg. of body weight of saidanimal.

References Cited by the Examiner UNITED STATES PATENTS 2,368,006 1/45Cusic 260-328 2,676,971 4/54 Cusic 260-2934 2,905,590 9/59 Schmutz167-65 2,964,556 12/60 Pribyl 167-65 3,031,459 4/62 Huebner 167-653,037,980 6/62 Hitchings 167-65 3,081,341 3/63 Mooradian 167-653,102,119 8/63 Knox 167-65 OTHER REFERENCES Seevers: Dental Abstr., vol.3, No. 8, August 1958, p. 481.

Kantz: I. Am. Med. Assoc., vol. 166, No. 9, pp. 1040 1041, Mar. 1, 1958.

Bloom: J. A. Chem. Soc., vol. 79, No. 18, p. 5072, 1957.

JULIAN S. LEVITT, Primary Examiner.

MORRIS O. WOLK, L. GOTTS, Examiners.

CERT

Patent No. 3,179,564

It is hereby certified ent req'1iring correction a corrected belowColumn 5 line 6 Signed and seale (SEAL) Attest:

ERNEST W. SWIDER A1 testing Officer IFICATE OF CORRECTION April 20, 1965Jean Schmutz s in the above numbered pat that error appear 5 Patentshould read as nd that the said Letter for "1990 C read 199 C.

d this 28th day of September 1965 EDWARD J. BRENNER Commissioner ofPatents

1. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FORM COMPRISING APHARMACEUTICAL CARRIER AND FROM ABOUT 5 TO ABOUT 100 MG. OF A COMPOUNDSELECTED FROM THE GROUP CONSISTING OF9-(N-METHYL-PIPERIDYL-2''-B-ETHYL)-THIOXANTHENE, AND THEPHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.